Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cachexia--a wasting condition--seriously impairs the quality of life of patients with advanced cancer. Previous studies have shown that several inflammatory cytokines mediate the development of cancer-associated cachexia. Experimentally, cachexia-like symptoms can be induced in tumor-bearing mice and treatment of such mice with chemotherapeutic agents reverses cachexia as a result of its therapeutic action. Nonetheless, cancer chemotherapy occasionally induces anorexia as an adverse reaction. For example, treatment with antitubulin taxanes reduces body weight in tumor-bearing mice more than healthy mice, even when the agents significantly reduce tumor growth. However, the complex relationship between cancer cachexia and the effects of anticancer drugs remains to be elucidated. This review outlines what is known about the development of cachectic reactions, especially in tumor-bearing mice, that occur during treatment with anticancer agents and highlights the clinical relevance of the information.
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PMID:Anticancer drugs that induce cancer-associated cachectic syndromes. 1211 61

Pivaloyloxymethyl butyrate (AN-9), an acyloxyalkyl ester prodrug of butyric acid (BA), has demonstrated greater potency than BA at inducing malignant cell differentiation and tumor growth inhibition and has demonstrated more favorable toxicological, pharmacological, and pharmaceutical properties than BA in preclinical studies. The principal objective of this study was to determine the feasibility of administering AN-9 as a 6-h i.v. infusion daily for 5 days every 3 weeks in patients with advanced solid malignancies. The study also sought to determine the principal toxicities and maximum tolerated dose of AN-9 on this intermittent schedule, as well as the effects of AN-9 on fetal hemoglobin production, a parameter indicative of RBC differentiation. None of the 28 patients treated with 85 total courses of AN-9 at dosages ranging from 0.047 to 3.3 g/m(2)/day every 3 weeks experienced dose limiting toxicity. Mild to moderate nausea, vomiting, hepatic transaminase elevation, hyperglycemia, fever, fatigue, anorexia, injection site reaction, diarrhea, and visual complaints were observed. Dose escalation of AN-9 was limited by the maximum feasible volume of its intralipid formulation vehicle that could be administered safely on this schedule, resulting in a maximum deliverable dose of 3.3 g/m(2)/day. There was no consistent increase in fetal hemoglobin with AN-9 treatment. A partial response was observed in a previously untreated patient with metastatic non-small cell lung cancer. Additional disease-directed clinical evaluations of AN-9 are necessary to establish the breadth of its antitumor activity and to assess its role as an effective differentiating agent.
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PMID:A phase I study of pivaloyloxymethyl butyrate, a prodrug of the differentiating agent butyric acid, in patients with advanced solid malignancies. 1211 14

Food intake is mainly controlled in the hypothalamus via a series of functionally related nuclei, including the ventromedial nucleus of hypothalamus (VMN) and the lateral hypothalamic area (LHA). Since food intake is the product of meal number and meal size, we investigated the role of the VMN and LHA in influencing these feeding indices and in mediating cancer anorexia in tumor-bearing (TB) rats, via temporarily inhibiting VMN or LHA. Adult male Fischer-344 rats (n = 23) inoculated with 106 MCA sarcoma cells were studied. When anorexia developed, rats were randomly assigned to stereotaxically located bilateral intra-VMN or intra-LHA microinjections of the neuronal blocker colchicine (CX; n = 6 each group) or saline (n = 6 and n = 5, respectively). Non TB rats (NTB; n = 7) served as controls. Food intake and feeding indices were recorded by a computerized device. At onset of anorexia, a reduction of meal number occurred, leading to reduced food intake. After inhibition of VMN activity by CX, meal number significantly increased, so that food intake increased and almost normalized. In contrast, intra-LHA microinjection of either CX or saline resulted in reduction of meal size, leading to reduced food intake and death. Findings suggest that VMN and LHA influence meal number and meal size, respectively. Since cancer anorexia mainly results from an initial reduction of meal number and the inhibition of VMN led to an increase in meal number, the early effect of tumor growth on VMN activity may be an early step leading to reduced food intake.
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PMID:VMN/LHA functional inhibition in tumor-bearing rats suggests hypothalamic involvement in cancer anorexia. 1250 74

Cancer cachexia has been suggested to be mediated by various cytokines derived either from tumor or host tissue. In the murine colon-26 (C-26) adenocarcinoma model IL-1, secreted by tumor-infiltrating mononuclear phagocytes, has an important role in induction of cancer cachexia. In order to suppress production of IL-1 in peritoneal macrophages we have used liposome-mediated gene transfer of the anti-inflammatory cytokine mIL-4, known as a potent inhibitor of IL-1 production. Balb/c mice were transfected by intraperitoneal inoculation of C-26 tumor cells. The mIL-4 transfected animals showed increased survival rate, delayed symptoms of cachexia and reduced anorexia in comparison with tumor-bearing control groups. However, tumor growth inhibition was not seen in mIL-4-transfected animals. Peritoneal macrophages from surviving mIL-4-transfected mice, when stimulated with LPS ex vivo, showed decreased IL-1 alpha production, 1672 +/- 202 pg/2 x 10(6) cells in contrast to tumor-bearing control animals, 3975 +/- 89 pg/2 x 10(6) cells, mock-transfected tumor-bearing animals 4004 +/- 174 pg/2 x 10(6) cells and tumor-free animals, 3142 +/- 60 pg/2 x 10(6) cells (p < 0.004). The present study demonstrates that in vivo gene transfer of an anti-inflammatory cytokine reduces cancer-associated cachexia by inhibition of IL-1 alpha production of tumor surrounding peritoneal macrophages, without a significant effect on tumor growth.
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PMID:In vivo gene transfer of murine interleukin-4 inhibits colon-26-mediated cancer cachexia in mice. 1252 62

Animals and humans respond to starvation with a complex neuroendocrine response that ultimately leads to an increase in appetite, a sparing of lean body mass (LBM) and burning of fat, and an overall decrease in basal metabolic rate. In contrast, cachexia is a pathological state of malnutrition associated with many infections and chronic diseases, wherein appetite is diminished concomitant with an increase in metabolic rate, and a relative wasting of LBM. In previous studies, we demonstrated that anorexia and weight loss in mouse cachexia models induced by lipopolysaccharide (LPS) administration and by tumor growth are ameliorated by central melanocortin-4 (MC4) receptor (MC4-R) blockade. In contrast to the results seen with MC4 blockade, melanocortin-3 (MC3) receptor knockout (MC3-RKO) mice show illness-induced anorexia and weight loss with LPS administration and with cytokine administration, and they have similar decreases in mobility. Both MC3-RKOs and MC4-RKOs have an intact corticosterone response and fever with LPS injection. In tumor models, we show that MC4-RKO mice resist the loss of LBM brought about by tumor growth, whereas MC3-RKO animals show enhanced tissue wasting. These data underscore the importance of central melanocortin signaling in weight homeostasis and demonstrate differential effects of MC3-R and MC4-R blockade on the development of cachexia.
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PMID:Differential role of melanocortin receptor subtypes in cachexia. 1263 36

Cancer cachexia is characterized by anorexia and intense peripheral catabolism. We examine the potential benefits of combination of different anabolic agents such as insulin and clenbuterol associated to prostaglandin synthesis inhibitor (naproxen) on tumor growth, cachexia and renal function in Walker 256 tumor-bearing rats (WK). Groups were separated into WK, and WK with naproxen (WK N) or naproxen plus clenbuterol (WK NCb) or naproxen plus clenbuterol plus insulin (WK NCbI). Treatment begins at the 4th day after tumor inoculation, at the 14th day they were killed, glycemia, lacticidemia, glycogen content from liver, soleus and gastrocnemius muscles, tumor mass, body weight and kidney function were determined. Glycemia and glycogen content were reduced and lacticidemia increased in WK (p<0.05) as compared to control rats. The glycogen content recovered in all treated groups. Tumor weight was significantly reduced by the different treatments. At the 14th weight change (carcass-initial body weight) in the control increased by 38% and in the WK -2%. Naproxen treatment (WK N) induced an increased by 14%. The inclusion of clenbuterol (WK NCb) and insulin (WK NCbI) by 38 and 41%, respectively. Mean glomerular filtration rate (GFR) increased in the WK (p<0.05) as compared to control, but in the WK NCb the GFR was similar to control. Our results suggest that naproxen is able to reduce tumor growth and its association with insulin and clenbuterol induce mass weight gain and recovery energy fuel.
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PMID:Naproxen, clenbuterol and insulin administration ameliorates cancer cachexia and reduce tumor growth in Walker 256 tumor-bearing rats. 1460 27

In cancer anorexia, a decrease in food intake (FI) occurs concomitant with changes in orexigenic peptides such as neuropeptide Y (NPY) and anorexigenic peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) and anorexigenic neurotransmitter serotonin. omega-3 Fatty acid (omega-3FA) inhibits cytokine synthesis, and delays tumor appearance, tumor growth, and onset of anorexia in tumor-bearing rats. We hypothesize that, in cancer anorexia, omega-3FA is associated with quantitative reversal of hypothalamic NPY, alpha-MSH, and serotonin receptor (5-HT(1B)-receptor) enhancing FI. Fischer rats were divided into: MCA tumor bearing fed chow (TB-Chow) or omega-3FA diet (TB-omega-3FA) and controls: non-tumor bearing fed chow (NTB-Chow) or omega-3FA diet (NTB-omega-3FA). Rats were euthanized at anorexia and brains were removed for hypothalamic immunohistochemical study, using NPY, alpha-MSH, and 5-HT(1B)-receptor-specific antibodies and slides assessed by image analysis. Immunostaining specificity was controlled by omission of primary or secondary antibodies and pre-absorption test. At anorexia, FI decreased (P < 0.05) in TB-Chow but did not change in TB-omega-3FA rats. In TB-omega-3FA vs. TB-Chow, NPY immunoreactivity increased 38% in arcuate nucleus (ARC; P < 0.05), and 50% in magnocellular paraventricular nucleus (mPVN; P < 0.05). alpha-MSH decreased 64% in ARC and 29% in mPVN (P < 0.05). 5-HT(1B)-receptor immunoreactivity decreased 13% only in supraoptic nucleus (P < 0.05). No immunoreactivity was found in the control sections. omega-3FA modified hypothalamic peptides and 5-HT-(1B)-receptor immunoreactivity at anorexia, concomitant with an increase in FI, were probably mediated by omega-3FA inhibition of tumor-induced cytokines.
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PMID:Effects of omega-3 fatty acids on orexigenic and anorexigenic modulators at the onset of anorexia. 1592 53

Previous studies in our laboratory have suggested that prostaglandin (PG) E2 is involved in anorexia/cachexia development in MCG 101 tumor-bearing mice. However, the role of COX pathways in the pathogenesis of cancer anorexia/cachexia is not fully resolved. In the present study, we investigated the role of PGE receptors subtype EP1 and EP3 on the development of anorexia in MCG 101-bearing mice. Our results show that the absence of host EP1 or EP3 receptors did not alter the magnitude of anorexia in tumor-bearers. However, anorexia in tumor-bearing EP1 and EP3 knockouts was not improved by indomethacin treatment as observed in wild type tumor-bearers. By contrast, indomethacin improved body composition similar in EP1 and EP3 knockouts as well as in wild type tumor-bearing animals and tumor growth was retarded in EP1 and promoted in EP3 knock outs. Our results demonstrate that host EP1 and EP3 receptors are involved in the control of local tumor growth, which translates into anorexia, this being the main cause of metabolic adaptive alterations to explain weight loss in this model. Brain EP1 and EP3 subtype receptors do not seem to directly control anorexia, which leaves EP2 and EP4 as potential candidates.
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PMID:Anorexia and cachexia in prostaglandin EP1 and EP3 subtype receptor knockout mice bearing a tumor with high intrinsic PGE2 production and prostaglandin related cachexia. 1594 39

Symptoms such as cough and hemoptysis in patients with lung cancer can be the consequence of local bronchopulmonary disease, tumor growth that leads to compression of surrounding structures, distant metastases, diverse systemic effects (anorexia, asthenia, weight loss), or paraneoplastic syndromes associated with tumor production of certain hormones. Approximately 10% of patients are asymptomatic at diagnosis. We report the case of a 77-year-old man with dyspnea, pleuritic chest pain, and lower limb edema. The patient died within a few days. The cause of the clinical picture was constrictive pericarditis secondary to metastases from lung carcinoma.
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PMID:[Constrictive pericarditis as the first sign of lung cancer]. 1712 98

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.
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PMID:Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. 1747 Jun 85


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